Allogeneic hematopoietic stem cell transplant (HCT) has the potential to cure patients with hematologic malignancies. However, HCT is associated with significant treatment related mortality (TRM) ranging from 20- 30%. (1). TRM is particularly high in patients with advanced age (hazard ratio 1.84, age >60 years vs. <20) and decreased physical function (hazard ratio 2.94, bottom quartile vs. top quartile). A major cause of TRM is graft- versus-host disease (GVHD), which affects 40-60% of patients. We hypothesis that age related microbiome changes will affect the HCT clinical outcomes, and in addition to age other factors such as diet, physical activity and the care environment can influence the microbiome profiles as well. Correlations between GVHD and disruptions in the gut microbiota have been reported in several studies, though it remains unclear how the microbiota causes or prevents GVHD. While lengthy hospitalizations are standard for HCT patients, caring for patients in a more normal care environment may preserve the natural microbiota. We hypothesized that shifting the care environment from the hospital to a more normal environment like the home can preserve the gut microbiota, thereby decreasing intestinal inflammation and GVHD. We have successfully piloted home HCT in a phase 1 trial (co-PIs Chao, Sung, clinicaltrials.gov NCT01725022) and have expanded our pilot into a randomized phase 2 study of home vs. standard care (clinicaltrials.gov NCT02218151, co-PIs Chao, Sung) funded by NCI 1R01CA203950 (PI Chao, co-I Sung). While age cannot be changed, other strategies to overcome the negative effects of aging-related microbiome changes can be the use of dietary and physical activity interventions. We have started a Phase I/II, pre- and peri-HCT optimization program (PPOP). PPOP has two pieces: a clinical component (C-PPOP), which establishes a new standard of care for the pre-HCT evaluation of all Duke HCT patients, and a research component (R-PPOP), which includes additional assessments and interventions to optimize health and function including diet and physical activity. In this proposed project we aim to: 1) evaluate the age related microbiome changes and their implications on HCT outcomes including TRM (primary endpoint), infections, GVHD, and immune function; 2) evaluate the effects of a dietary and physical activity intervention on the aged microbiome and implications on HCT outcomes. For this study will be able to utilize existing samples from the Duke Hematologic Malignancies Biorepository. This study can provide new insights into the underlying mechanisms of GVHD in Leukemia and other malignant diseases. If successful, this study will identify the impact of age related microbiome changes on HCT outcomes and the immune system, as well as strategies to target the aged microbiome to promote better outcomes for HCT patients.